【摘要】：血管生成(Angiogenesis)是指從已有的血管中發(fā)芽生成新血管的過(guò)程,腫瘤的生長(zhǎng)、侵襲和轉(zhuǎn)移依賴(lài)于新生血管的形成。抑制腫瘤介導(dǎo)的血管生成,阻斷癌細(xì)胞的營(yíng)養(yǎng)途徑,就可以有效抑制癌細(xì)胞增殖。血管內(nèi)皮生長(zhǎng)因子(Vascular endothelial growth factor, VEGF)是腫瘤新生血管形成中的關(guān)鍵性促血管生長(zhǎng)因子,可在體內(nèi)誘導(dǎo)血管新生。目前已經(jīng)得到公認(rèn),VEGF對(duì)內(nèi)皮細(xì)胞的分化、增殖作用是由血管內(nèi)皮生長(zhǎng)因子受體-2(Vascular endothelial growth factor receptor-2, VEGFR-2)介導(dǎo)的。因此,在抗腫瘤藥物研發(fā)中,針對(duì)VEGFR-2的酪氨酸激酶是一個(gè)關(guān)鍵的藥物作用靶點(diǎn),VEGFR-2酪氨酸激酶抑制劑也成為了抗腫瘤藥物研究的一個(gè)重要方向。 本研究的目的是合成各種新型吲哚-苯并咪唑類(lèi)衍生物,通過(guò)篩選獲得具有一定活性和自主知識(shí)產(chǎn)權(quán)的化合物,用于進(jìn)一步的活性研究。本研究主要進(jìn)行了以下方面的工作： 1對(duì)已設(shè)計(jì)出的一系列結(jié)構(gòu)新穎、未見(jiàn)報(bào)導(dǎo)的新型VEGFR-2酪氨酸激酶抑制劑進(jìn)行逆合成路線(xiàn)分析,根據(jù)反應(yīng)可行性、路線(xiàn)復(fù)雜性、操作安全性等,針對(duì)每個(gè)化合物的結(jié)構(gòu)設(shè)計(jì)出盡可能合理可行的合成路線(xiàn)。 2根據(jù)設(shè)計(jì)出的合成路線(xiàn),對(duì)每種化合物進(jìn)行合成。通過(guò)不同的合成路線(xiàn)分別合成了吲哚-3-甲酸、吲哚-3-乙酸、吲哚-3-丙酸、2-吲哚酮-3-丙酸、2-甲基吲哚-3-乙酸和5-甲氧基-2-甲基吲哚-3-乙酸等吲哚酸類(lèi)化合物。 3合成的這幾種吲哚酸再分別與鄰苯二胺鹽酸鹽、4-甲基鄰苯二胺和3,4-二氨基苯甲酸乙酯在多聚磷酸的催化下發(fā)生脫水環(huán)合反應(yīng),生成九種目標(biāo)產(chǎn)物吲哚-苯并咪唑類(lèi)衍生物。 4由(R)-3-喹核醇經(jīng)酯交換法和乙酸酐法兩種方法合成了(R)-3-乙酸奎寧環(huán)基酯,并比較得知,乙酸酐法操作簡(jiǎn)單、收率高。
[Abstract]:Angiogenesis (Angiogenesis) is the process of sprouting new blood vessels from existing vessels. Tumor growth, invasion and metastasis depend on the formation of neovascularization. Inhibition of tumor-mediated angiogenesis, blocking the nutritional pathway of cancer cells, can effectively inhibit the proliferation of cancer cells. Vascular endothelial growth factor (Vascular endothelial growth factor, VEGF) is a key angiogenic factor in tumor angiogenesis, which can induce angiogenesis in vivo. It has been recognized that the differentiation and proliferation of endothelial cells by VEGF is mediated by vascular endothelial growth factor receptor-2 (Vascular endothelial growth factor receptor-2, VEGFR-2. Therefore, tyrosine kinase targeting VEGFR-2 is a key drug target in the research and development of antitumor drugs. VEGFR-2 tyrosine kinase inhibitor has also become an important research direction of antitumor drugs. The aim of this study was to synthesize various new indole-benzimidazole derivatives and obtain compounds with certain activity and independent intellectual property rights for further study. The main work of this study is as follows: 1 A series of novel VEGFR-2 tyrosine kinase inhibitors that have been designed have been studied by reverse synthesis route analysis, according to the feasibility of the reaction and the complexity of the route, a series of novel VEGFR-2 tyrosine kinase inhibitors have been designed. According to the structure of each compound, the synthetic route is designed as reasonable and feasible as possible. 2 according to the designed synthetic route, each compound is synthesized. Indole-3-formic acid, indole-3-acetic acid, indole-3-propionic acid, 2-indole-3-propionic acid were synthesized by different synthetic routes. 2-methylindole-3-acetic acid and 5-methoxy-2-methyl-indole-3-acetic acid and other indoleic acid compounds. (3) the synthesized indoleic acid reacts with o-phenylenediamine hydrochloride, 4-methyl-o-phenylenediamine, and ethyl 3o 4-diaminobenzoate respectively under the catalysis of polyphosphoric acid. Nine target products of indole-benzimidazole derivatives were obtained. 4 (R) 3-quinine cycloester was synthesized by transesterification method and acetic anhydride method from (R) 3-quinolinol. It was found that the acetic anhydride method was simple and the yield was high.
【學(xué)位授予單位】：青島科技大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R914.5

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